The present proposal describes an approach to an orally active agent against both Influenza A and B. Influenza virus transcription occurs by a unique mechanism. Both dinucleoside monophosphate analogues of the type ApG and analogues of the MRNA cap structure of the type 7-methyl-GMP have ben found to inhibit viral transcription in vitro, but all of these compounds are inactive in vivo. The first goal is to render these compounds cell permeable by chemical modifications utilizing a large database previously obtained by Gilead's laboratory from the evaluation of hundreds of compounds for cellular permeation with a fluorescent microscopy technique to determine cellular localization of fluorescently labelled nucleic acid analogues. The compounds found active in the in vitro transcriptase assay will subsequently be evaluated in tissue culture and, if warranted, in vitro in an influenza animal model.
